Abstract: FR-PO715
Lack of Complement Factor H Contributes to Endothelial Cell Injury in Shiga Toxin Haemolytic Uraemic Syndrome
Session Information
- Glomerular Diseases: Podocyte Biology - I
November 04, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1304 Glomerular Diseases: Podocyte Biology
Authors
- Bowen, Emily Elizabeth, University of Bristol Faculty of Health Sciences, Bristol, Bristol, United Kingdom
- Hurcombe, Jenny, University of Bristol Faculty of Health Sciences, Bristol, Bristol, United Kingdom
- Barrington, Fern, University of Bristol Faculty of Health Sciences, Bristol, Bristol, United Kingdom
- Farmer, Louise K., University of Bristol Faculty of Health Sciences, Bristol, Bristol, United Kingdom
- Ortiz-Sandoval, Carolina G., SickKids Research Institute, Toronto, Ontario, Canada
- Bruno, Valentina, SickKids Research Institute, Toronto, Ontario, Canada
- Rostam Shirazi, Niyousha, SickKids Research Institute, Toronto, Ontario, Canada
- Welsh, Gavin Iain, University of Bristol Faculty of Health Sciences, Bristol, Bristol, United Kingdom
- Licht, Christoph, SickKids Research Institute, Toronto, Ontario, Canada
- Saleem, Moin, University of Bristol Faculty of Health Sciences, Bristol, Bristol, United Kingdom
- Coward, Richard, University of Bristol Faculty of Health Sciences, Bristol, Bristol, United Kingdom
Background
Haemolytic uraemic syndrome (HUS) is a thrombotic microangiopathy that has a predilection for the kidney. In 90% of cases, HUS follows gastroenteritis secondary to infection with Shiga toxin (Stx) producing bacteria such as Escherichia coli.STEC HUS is the leading cause of acute kidney injury in children with a mortality of 5%. We have previously shown endothelial cell complement activation in a PodGb3 mouse model of STEC HUS.Here we build upon these findings to show that a reduction in glomerular endothelial CFH occurs both in our animal model and in-vitro co-culture models.
Methods
To demonstrate that the podocyte Stx receptor (Gb3) is sufficient to trigger the development of HUS, we used conditional gene targeting to engineer human Gb3 expression specifically in the podocytes of mice (PodGb3). Using an in-vitro human glomerular cell co-culture model we evaluated the effects of Stx on endothelial cell injury, complement activation (C3b, C5b-9) and regulation (CD46, CD55, CFH).
Results
Following intraperitoneal Stx, PodGb3 mice recapitulate all of the histopathological features of HUS. Further interrogation demonstrated glomerular endothelial cell complement activation, loss of CFH protection and rescue of the HUS phenotype following C5 inhibitor treatment. Interestingly, in co-culture studies Stx caused a reduction in glomerular endothelial CFH that was only seen in the presence of co-culture with podocytes.
Conclusion
These observations provide compelling evidence for the importance of podocyte-glomerular endothelial cell cross-talk in the development of STEC HUS and suggest a possible therapeutic role for complement inhibition in patients with this devastating disease.
Funding
- Other NIH Support